December 1979
TheJournalofPEDIATRICS
1043
Plasma carnitine levels during intravenous feeding of the neonate The premature inJ'ant has a limited capacity for fatty acid oxidation. This study shows that solutions commonly used for intravenous feedings in the newborn infant contain no carnitine. Infimts maintained on this solution have significantly lower total, j[?ee, and acvlcarnitine levels as compared to when they are Jed oral!v with expressed human milk or a proprietary formula, which is known to contain carnitine. The exogenous supply of carnitine to the premature infant may have a significant influence on the ability to stimulate optimal fatty acid oxidation.
David Sehiff, M.D., Ph.D., F.R.C.P.(C),* George Chan, M.Se., David Seeeombe, M.Se., and P e t e r Hahn, M.D., Ph.D., F.R.C.P.(C),
MRC (Canada), E d m o n t o n , A l b e r t a , C a n a d a
IN tHE IMMEDIATE NEWBORN PERIOD the main source Of energy is fat. 1This has been substantiated by the rapid postnatal rise in blood levels of free fatty acids, 2 glycerol.' and the slow rise of ketones? The optimum oxidation of fatty acids requires carnitine, which, in the form of acylcarnitine, transfers FFA into mitochondria where they are recombined with CoA to form Acyl-CoA.' The blood levels of ketones and acylcarnitine reflect the rate of FEA utilization in the liver? The acylcarnitines consist mostly of acetylcarnitine,~ probably formed in the liver to relieve the acetyl pressure,: due to the high rate of FFA oxidationl In most mammalian species, the blood levels of both total and acylcarnitine rise rapidly after birth? -~~In man the urinary excretion of acylcarnitine is increased at the same time." The enzymes involved in acylcarnitine formation (carnitine-acetyl-, octanoyl, palmitoyl-l-, and palmitoyl-2-transferase) increase perinatally in both liver and heart in several mammalian species. ~-' No data are From the Departments of Pediatrics, Obstetrics and Gynecology, Universi(v of Alberta, and University o[ British Columbia. Supported b)" Special Services Grant No. 7068 Universi(v of AIberta Hospital (D. S.); Medical Research Council ?[" Canada Granl No. 686162 (P.H.). *Reprint address: Department of Pediatrics Universi(v oj Alberta, Edmonton, Alberta T6G 2G3, Canada.
0022-3476/79/121043+04500.40/0 9 1979 The C. V. Mosby Co.
available for human newborn infants, although fetal values have been repoi'ted? ~' Thei'e are no repoi'ted data on the metabolism of carnitine in very small newborn infants, nor are data available on the requirements for carnitine under special circumstances. Carnitine is known to be present in human milk (1 mg/dl) and in Similac (l mg/dl), and recently has been demonstrated tO be absent in soybean formulas. H. 1:~ Abbreviations used EBM: expressed human milk FFA: free fatty acids With the advent of" intravenotis alimentation, and in pai-ticular the Use of Intralipid as a fat source, the question as to whether fatty acid oxidation is compromised in small newborn infants has been raised. 1~ The newborn infant does have a limited capacity Of fatty acid oxidation. ':' The present study was undertaken to determine: (1) the presence or absence of carnitine in intravenous fat and intravenous amino acid solution; and (2) the plasma carnitine levels in newborn infants fed intravenously.
MATERIALS AND METHODS Techniques. Free and total carnitine concentrations were determined in 50/LI of plasma. ''~ Acylcarnitine was calculated from the difference between the total and free
VoL 95, No. 6, pp. 1043-1046
I044
S c h ! f f et al.
The Journal of Pediatrics December 1979
40-
30-
20LU Z I--
Intralipid Similac EBM
< o
A
10/
o~ e
O/
Total Carnitine ~
__.
Sp
I
Acyl Carnitine
/eS les'-
i/C//////////{///////]
I
o
go
io
60
go
DAYS
Figure. lrifant Girl F was born at 30 weeks'gestation weighing 990 gm. Her major clinical problems was apneic spells. She developed necrotizing enterocolitis on two separate occasions seven days apart. During each of these periods she received Travasol and Intralipid for a total of 43 days. Oral feeds were in the form of EBM and Similac.
Table. Serum levels of carnitine in 33 newborn infants during intravenous feeds and when fed human milk or Similac
Total carnitine (/,M/1) Acylcainitine (/,M/1) Free carnitine (yM/l)
Intravenous ,lee& O~ean • SD)
Milk jeeds (mean .• SD)
15.9 • 5.0
29.1 + 8.7
< 0.001
4~9 _+ 2.0
7.5 _+ 3.1
< 0.005
10.5 • 3.6
19.4 + 6.9
< 0.001
carnitine levels. The iotal carnitine concentration was also assayed in Travasol and,in lntralipid. I n f a n t s Studied. A total of 33 infants admitted to the Neona{al Intensive Care. Unit of the University of Alberta Hospital Who requ!red peripheral intravenous alimentation for various reasons were studied. The infants ranged in gestational age from 26 to 40 weeks, with a mean of 31.3 weeks: the weights ranged f r o ~ 8 0 0 to 4;300 g, with a mean of 1,525.0 g. Samples of blood were obtained from the infants prior tO the initiation Of intravenous feeding, during the period of time that they were maintained solely on intravenous feeding, and in the period9 of time when
they were fed orally. The intravenous feedings included Travasol. which is a mixture of crystalline amino acids. ghe amount of the amino acid solution received was increased gradually from 0.5 g m / k g / d a y to a total of 2.5 g m / k g / d a y . The fat source was Intralipid. the inital dose being 0.5 g m / k g / d a y , and increased to a maximum of 4 g m / k g / d a y depending on the plasma triglyceride levels. which were maintained below 100 m g / d l Venous blood. 1.5 ml. was taken into an E D T A tube. immediately spun down. and 200 /,1 of plasma were withdrawn and deep frozen until assayed for carnitine. 1~ The r e m a i n d e ~ o f the plasma was used to monitor the infant's triglyceride levels 1~ and ketone bodies, is The routine monitoring of infants on intravenous alimentation in our unit includes a measurement of free fatty acids. triglycerides, and ketone bodies, and requires no more than the amount described. Fhe addition of carnitine determination did not require additional blood. Informed patent-al consent ts obtained for intravenous feeding and rou,tine monitoring of the infants. Results. Intravenous solutions of tntralipid and Travasol contained less than 1 >M/1 of carnitme. The Table demonstrates the mean ~ SD levels of total carnitine, acylcarnitine, and free carnitine measured in these infants during the period of total intravenous alimentation and in the period when they were realimented on EBM or
Volume 95 Number 6
proprietary formula. There were significant differences in the three values during the two periods o f study. DISCUSSION These studies demonstrate that the intravenous fat. Intralipid. and an amino acid solution. Travasol. do not contam carnitine. Furthermore. the sti3dies show that the blood carnitine levels in infants are to a large extent dependent on an external source of carnitine. However. even when essentially no carnitine is given, the blood levels remain relatively constant, although very low. This suggests that carnitine is being supplied endogenously, either from some depot ~muscle or liver) or possibly from synthesis within the liver. The synthesis of carnitine requires lysme, methionine, a n d / o r choline. 1~All o f these amino acids are present in the Travasol solution in sufficient amounts to ensure biosynthesis. Clearly the higher levels achieved are from an exogenous source such as EBM or proprietary formulas. The Figure illustrates an example of such an instance. Wherein an infant had two bouts of necrotizing enterocolitis and required two courses of mtravenous alimentati0n followed by two attempts at oral alimentation, in the first instance with EBM and in the second instance with Similac. During both periods of intravenous alimentation the carnitine levels fell to extremely low values, and in both periods o f oral alimentation the carnitine levels rose quite strikingly. In one o f the infants studied, who ultimately died. the carnitine levels continued to fall despite repeated attempts at oral alimentation This infant had necrottzing enterocolitis which did not respond to therapy, and ultimately he developed elevated liver enzymes and persistent jaundice. The failure to raise carnitine levels suggested either hepatic failure with no fatty acid oxidation, or failure of absorption of carniune through a diseased bowel. The gradual fall in blood carnttine levels in this infant indicates that even with no external supply of carnitine, the neonate is capable of maintaining low but stable concentrations in the range 15 to 20 aM/1. unless there is bowel or liver pathology or both. A positive correlation has been shown to exist between serum levels of belahydroxybutyratc and acylcarnitine11: as expected, a negative correlation has been found between the ketone and free carnitine levels. -~~No such correlation was found in this study, and this may be due to its design. Sampling for blood did not occur consistently at a time when Intralipid was being infused. Feeding nutrients that do not contain carnitine leads to a fall in blood levels of total carnitine. This is true for soybean-based formula 1:' and for intravenous alimentation. In neither case has a clinical problem owing to a lack
Plasma carnitine during intravenous jbeding
10 4 5
of carnitine been described. This suggests that under normal ctrcumstances, endogenous synthesis of carnitine occurs, even in the very premature infant. On the other hand. there have been reports of the toxic effects of Intralipid in very small infants. ~1 These may have been due, at least in part, to the lack of carnitine and thus to the relative inability to utilize lipid s. This hypothesis is also supported by the fact that in both this work and in the study of Novak et a]," levels of acylcarnitine were very tow when compared to those of normally fed infants. The present study raises the question of the possible therapeutic benefits of supplementing carnitine in the intravenously alimented child. The authors thank all the nui'ses of the Neonatal Intensive care Unit of the University Of Alberta Hospital for their assistance in collecting specimens, Mrs. Kathy Merrills and Miss Leslie Hart of the University of Alberta, and Mrs. Frieda Ann Smalle from the Department of Developmental Medicine, University of British Columbia, for laboratory assistance. REFERENCES
1. Hahn 0, and Koldovsky O: Utilization of nutrients during postnaial development, Oxford, 1966, Pergamon Press, Inc. 2. Van Duyne CM, and Havel R J: Plasma unesterified fatty acid in fetal and neonatal life, Proc Soc Exp Biol 102:299, 1959. 3. Melichar V, Drahota Z, and Hahn P: Changes in the blood levels of acetoacetate and ketone bodies in newborn infants, Biol Neonate 8:348, 1965. 4, Fritz [B, and Yu KTN. Long chain carnitine acyl transferase and the role o}"acylcarnitine derivatives in the catalytic increase of long chain fatty acid oxidation, J Lipid Res 4:279. 1963. 5. Seccombe DW, Hahn P, and Novak M: The effect of diet and development on blood levels of free and esterified carnitine in the rat, Biochim Biophys Acta 528:683, 1978. 6. Bohmer T: Tissue concentration of activated fatty acids (acylcarnitines) and the regulation of fatty acid metabolism, Biochem Biophys Acta 144:259, 1967. 7. Snoswell AM, and Henderson GD: Aspects of carnitine ester metabolism in sheep liver, Biochem J 119:59, 1970. 8. Hahn P, and Skala J: Carnitine and brown adipose tissue metabolism in the rat during development, Biochem J 127:107, 1972. 9. Hahn P, and Skala J: The role ofcarnitine in brown adipose tissue of suckling rats, Comp Biochem Physiol 513i507, 1975. 10. Hahn P, and Seccombe D: Control of blood carnitine and carnitine acyltransferase in the perinatal period, New York, Academic Press, Inc., (in press). 11. Novak M. Wieser PB, Bach M, and Hahn P: Acteylcarnitine and free carnitine in body fluids before and after birth, Pediatr Res 13:10, 1979. 12. Bieber LL, Markwell MAK, Blair M, and Helmrath TA: Studies on the development of carnitine palmitoyl transferase and fatty acid oxidation in liver mitochondria of neonatal pigs, Biochem Biophys Acta 326:145, 1973.
1046
S c h i f f et al.
13. Schmidt-Sommerfeld E, Novak M, Penn D, Weiser PB, Buch M, and Hahn P: Carnitine and the development of newborn adipose tissue, Pediatr Res 12:660, 1968. 14. Schiff D, Chan G, and Andrew G: Metabolism of intravenously adminstered lipid in the newborn, in Stern L, editor: Intensive care in the newborn II., New York, 1978, Masson Publishing USA, Inc., p 267. 15. Andrew G, Chan G, and Schiff D: Lipid metabolism in the neonate, lIl. The ketogenic effect of Intralipid infusion in the neonate, J Pediatr 92:995, 1978. 16. McGarry JD, and Foster DW: An improved and simplified radioisotopic.assay for the determination of free and estertried carnitine, J Lipid Res 17:277, 1976. 17. Stone M, and Thorpe JL: A new technique for the investi-
The Journal of Pediatrics December 1979
18.
19.
20.
21.
gation of low density lipo-proteins in health and disease, Clin Chim Acta 14:812, 1966. Persson B: Determination of plasma acetoacetate and B-hydroxybutyrate in newborn infants by an enzymatic fluorometric method, Scand J Clin Invest 25:9, 1970. Cox RA, and Hoppel CL: Biosynthesis of carnitine and 4-N-trimethylaminobutyrate from lysine, Biochem J 136:1075, 1973. Frohlich J, Seccombe DW, Hahn P, Dodek P, and Hynie I: The effect of fasting on free and esterfied carnitine levels in human serum and urine, Metabolism 27:555, 1978. Postuma R, and Trevenen CL: Liver disease in infants receiving total parenteral" nutrition, Pediatrics 63:110, 1979.
Brief clinical and laboratory observations Full recovery from prolonged brainstem failure following intraventricular hemorrhage Joseph F. Pasternak, M.D., and Joseph J. Volpe, M.D.,* St. Louis, Mo.
P E R I V E N T R i C U L A R - I N T R A V E N T R 1 C U L A R HEMORRHAGE has been shown recently to be an extraordinarily c o m m o n lesion in the premature i n f a n t J ~ Although the majority of infants with hemorrhage survive, many die or sustain significant permanent neurologic disability. These severely affected infants usually exhibit distinct neurologic manifestations around the time of the hemorrhage, 1 ~ whereas those less severely affected usually have more subtle or, indeed, no abnormal neurologic findings, 1 ~, ~ Although it is generally recognized that a serious neonatal neurologic syndrome does not invariably presage a poor outcome, it is not clear from available From the Edward Mallinckrodt Department o[: Pediatrics and the Department of Neurology and Neurosurgel T (Neurology), Washington University School of Medicine, and the Division o f Neurology, St. Louis Children's Hospital. Supported in part b)~ The Allen P. and Josephine B. Green Foundation, M e x i c ~ Mo. Dr. Volpe is a recipient of a Research Career Development A ward (1-K4-HD 70608)frorn..the National Institutes t?f Health. *Reprint address: St. Louis Children's Hospital 500 S. Kingshighwa)', P. O. Box 14871, St. Louis, MO 63178.
information how serious a neurologic deterioration may occur and still be compatible with a favorable outcome. We report a premature infant with intraventricular hemorrhage who had a syndrome of essentially total brainstem failure but who recovered spontaneously and Abbreviations used CSF: cerebrospinal fluid CT: computerized tomography CPA~: continuous positive airway pressure EEG: electroencephalogram has made nearly normal developmental progress over the first 12 months. The particular importance of this case relates to the implicatidns of this clinical course for therapeutic and ethical decision-making in the manage,ment of the newborn infant with essentially total brainstem failure. CASE REPORT This female infant weighed 2,300 gm at birth after an uncomplicated 35-week gestation in a 23-year-old gravida 4, para 3 mother. Amniotic membranes ruptured spontaneously 48 hours prior to delivery and produced ciear find. Attempted induction of labor with pitocin failed on two successive days. On the
0022-3476/79/121046 + 04500.40/0 9 1979 The C. V. Mosby Co.
TheJournalofPEDIATRICS
1043
Plasma carnitine levels during intravenous feeding of the neonate The premature inJ'ant has a limited capacity for fatty acid oxidation. This study shows that solutions commonly used for intravenous feedings in the newborn infant contain no carnitine. Infimts maintained on this solution have significantly lower total, j[?ee, and acvlcarnitine levels as compared to when they are Jed oral!v with expressed human milk or a proprietary formula, which is known to contain carnitine. The exogenous supply of carnitine to the premature infant may have a significant influence on the ability to stimulate optimal fatty acid oxidation.
David Sehiff, M.D., Ph.D., F.R.C.P.(C),* George Chan, M.Se., David Seeeombe, M.Se., and P e t e r Hahn, M.D., Ph.D., F.R.C.P.(C),
MRC (Canada), E d m o n t o n , A l b e r t a , C a n a d a
IN tHE IMMEDIATE NEWBORN PERIOD the main source Of energy is fat. 1This has been substantiated by the rapid postnatal rise in blood levels of free fatty acids, 2 glycerol.' and the slow rise of ketones? The optimum oxidation of fatty acids requires carnitine, which, in the form of acylcarnitine, transfers FFA into mitochondria where they are recombined with CoA to form Acyl-CoA.' The blood levels of ketones and acylcarnitine reflect the rate of FEA utilization in the liver? The acylcarnitines consist mostly of acetylcarnitine,~ probably formed in the liver to relieve the acetyl pressure,: due to the high rate of FFA oxidationl In most mammalian species, the blood levels of both total and acylcarnitine rise rapidly after birth? -~~In man the urinary excretion of acylcarnitine is increased at the same time." The enzymes involved in acylcarnitine formation (carnitine-acetyl-, octanoyl, palmitoyl-l-, and palmitoyl-2-transferase) increase perinatally in both liver and heart in several mammalian species. ~-' No data are From the Departments of Pediatrics, Obstetrics and Gynecology, Universi(v of Alberta, and University o[ British Columbia. Supported b)" Special Services Grant No. 7068 Universi(v of AIberta Hospital (D. S.); Medical Research Council ?[" Canada Granl No. 686162 (P.H.). *Reprint address: Department of Pediatrics Universi(v oj Alberta, Edmonton, Alberta T6G 2G3, Canada.
0022-3476/79/121043+04500.40/0 9 1979 The C. V. Mosby Co.
available for human newborn infants, although fetal values have been repoi'ted? ~' Thei'e are no repoi'ted data on the metabolism of carnitine in very small newborn infants, nor are data available on the requirements for carnitine under special circumstances. Carnitine is known to be present in human milk (1 mg/dl) and in Similac (l mg/dl), and recently has been demonstrated tO be absent in soybean formulas. H. 1:~ Abbreviations used EBM: expressed human milk FFA: free fatty acids With the advent of" intravenotis alimentation, and in pai-ticular the Use of Intralipid as a fat source, the question as to whether fatty acid oxidation is compromised in small newborn infants has been raised. 1~ The newborn infant does have a limited capacity Of fatty acid oxidation. ':' The present study was undertaken to determine: (1) the presence or absence of carnitine in intravenous fat and intravenous amino acid solution; and (2) the plasma carnitine levels in newborn infants fed intravenously.
MATERIALS AND METHODS Techniques. Free and total carnitine concentrations were determined in 50/LI of plasma. ''~ Acylcarnitine was calculated from the difference between the total and free
VoL 95, No. 6, pp. 1043-1046
I044
S c h ! f f et al.
The Journal of Pediatrics December 1979
40-
30-
20LU Z I--
Intralipid Similac EBM
< o
A
10/
o~ e
O/
Total Carnitine ~
__.
Sp
I
Acyl Carnitine
/eS les'-
i/C//////////{///////]
I
o
go
io
60
go
DAYS
Figure. lrifant Girl F was born at 30 weeks'gestation weighing 990 gm. Her major clinical problems was apneic spells. She developed necrotizing enterocolitis on two separate occasions seven days apart. During each of these periods she received Travasol and Intralipid for a total of 43 days. Oral feeds were in the form of EBM and Similac.
Table. Serum levels of carnitine in 33 newborn infants during intravenous feeds and when fed human milk or Similac
Total carnitine (/,M/1) Acylcainitine (/,M/1) Free carnitine (yM/l)
Intravenous ,lee& O~ean • SD)
Milk jeeds (mean .• SD)
15.9 • 5.0
29.1 + 8.7
< 0.001
4~9 _+ 2.0
7.5 _+ 3.1
< 0.005
10.5 • 3.6
19.4 + 6.9
< 0.001
carnitine levels. The iotal carnitine concentration was also assayed in Travasol and,in lntralipid. I n f a n t s Studied. A total of 33 infants admitted to the Neona{al Intensive Care. Unit of the University of Alberta Hospital Who requ!red peripheral intravenous alimentation for various reasons were studied. The infants ranged in gestational age from 26 to 40 weeks, with a mean of 31.3 weeks: the weights ranged f r o ~ 8 0 0 to 4;300 g, with a mean of 1,525.0 g. Samples of blood were obtained from the infants prior tO the initiation Of intravenous feeding, during the period of time that they were maintained solely on intravenous feeding, and in the period9 of time when
they were fed orally. The intravenous feedings included Travasol. which is a mixture of crystalline amino acids. ghe amount of the amino acid solution received was increased gradually from 0.5 g m / k g / d a y to a total of 2.5 g m / k g / d a y . The fat source was Intralipid. the inital dose being 0.5 g m / k g / d a y , and increased to a maximum of 4 g m / k g / d a y depending on the plasma triglyceride levels. which were maintained below 100 m g / d l Venous blood. 1.5 ml. was taken into an E D T A tube. immediately spun down. and 200 /,1 of plasma were withdrawn and deep frozen until assayed for carnitine. 1~ The r e m a i n d e ~ o f the plasma was used to monitor the infant's triglyceride levels 1~ and ketone bodies, is The routine monitoring of infants on intravenous alimentation in our unit includes a measurement of free fatty acids. triglycerides, and ketone bodies, and requires no more than the amount described. Fhe addition of carnitine determination did not require additional blood. Informed patent-al consent ts obtained for intravenous feeding and rou,tine monitoring of the infants. Results. Intravenous solutions of tntralipid and Travasol contained less than 1 >M/1 of carnitme. The Table demonstrates the mean ~ SD levels of total carnitine, acylcarnitine, and free carnitine measured in these infants during the period of total intravenous alimentation and in the period when they were realimented on EBM or
Volume 95 Number 6
proprietary formula. There were significant differences in the three values during the two periods o f study. DISCUSSION These studies demonstrate that the intravenous fat. Intralipid. and an amino acid solution. Travasol. do not contam carnitine. Furthermore. the sti3dies show that the blood carnitine levels in infants are to a large extent dependent on an external source of carnitine. However. even when essentially no carnitine is given, the blood levels remain relatively constant, although very low. This suggests that carnitine is being supplied endogenously, either from some depot ~muscle or liver) or possibly from synthesis within the liver. The synthesis of carnitine requires lysme, methionine, a n d / o r choline. 1~All o f these amino acids are present in the Travasol solution in sufficient amounts to ensure biosynthesis. Clearly the higher levels achieved are from an exogenous source such as EBM or proprietary formulas. The Figure illustrates an example of such an instance. Wherein an infant had two bouts of necrotizing enterocolitis and required two courses of mtravenous alimentati0n followed by two attempts at oral alimentation, in the first instance with EBM and in the second instance with Similac. During both periods of intravenous alimentation the carnitine levels fell to extremely low values, and in both periods o f oral alimentation the carnitine levels rose quite strikingly. In one o f the infants studied, who ultimately died. the carnitine levels continued to fall despite repeated attempts at oral alimentation This infant had necrottzing enterocolitis which did not respond to therapy, and ultimately he developed elevated liver enzymes and persistent jaundice. The failure to raise carnitine levels suggested either hepatic failure with no fatty acid oxidation, or failure of absorption of carniune through a diseased bowel. The gradual fall in blood carnttine levels in this infant indicates that even with no external supply of carnitine, the neonate is capable of maintaining low but stable concentrations in the range 15 to 20 aM/1. unless there is bowel or liver pathology or both. A positive correlation has been shown to exist between serum levels of belahydroxybutyratc and acylcarnitine11: as expected, a negative correlation has been found between the ketone and free carnitine levels. -~~No such correlation was found in this study, and this may be due to its design. Sampling for blood did not occur consistently at a time when Intralipid was being infused. Feeding nutrients that do not contain carnitine leads to a fall in blood levels of total carnitine. This is true for soybean-based formula 1:' and for intravenous alimentation. In neither case has a clinical problem owing to a lack
Plasma carnitine during intravenous jbeding
10 4 5
of carnitine been described. This suggests that under normal ctrcumstances, endogenous synthesis of carnitine occurs, even in the very premature infant. On the other hand. there have been reports of the toxic effects of Intralipid in very small infants. ~1 These may have been due, at least in part, to the lack of carnitine and thus to the relative inability to utilize lipid s. This hypothesis is also supported by the fact that in both this work and in the study of Novak et a]," levels of acylcarnitine were very tow when compared to those of normally fed infants. The present study raises the question of the possible therapeutic benefits of supplementing carnitine in the intravenously alimented child. The authors thank all the nui'ses of the Neonatal Intensive care Unit of the University Of Alberta Hospital for their assistance in collecting specimens, Mrs. Kathy Merrills and Miss Leslie Hart of the University of Alberta, and Mrs. Frieda Ann Smalle from the Department of Developmental Medicine, University of British Columbia, for laboratory assistance. REFERENCES
1. Hahn 0, and Koldovsky O: Utilization of nutrients during postnaial development, Oxford, 1966, Pergamon Press, Inc. 2. Van Duyne CM, and Havel R J: Plasma unesterified fatty acid in fetal and neonatal life, Proc Soc Exp Biol 102:299, 1959. 3. Melichar V, Drahota Z, and Hahn P: Changes in the blood levels of acetoacetate and ketone bodies in newborn infants, Biol Neonate 8:348, 1965. 4, Fritz [B, and Yu KTN. Long chain carnitine acyl transferase and the role o}"acylcarnitine derivatives in the catalytic increase of long chain fatty acid oxidation, J Lipid Res 4:279. 1963. 5. Seccombe DW, Hahn P, and Novak M: The effect of diet and development on blood levels of free and esterified carnitine in the rat, Biochim Biophys Acta 528:683, 1978. 6. Bohmer T: Tissue concentration of activated fatty acids (acylcarnitines) and the regulation of fatty acid metabolism, Biochem Biophys Acta 144:259, 1967. 7. Snoswell AM, and Henderson GD: Aspects of carnitine ester metabolism in sheep liver, Biochem J 119:59, 1970. 8. Hahn P, and Skala J: Carnitine and brown adipose tissue metabolism in the rat during development, Biochem J 127:107, 1972. 9. Hahn P, and Skala J: The role ofcarnitine in brown adipose tissue of suckling rats, Comp Biochem Physiol 513i507, 1975. 10. Hahn P, and Seccombe D: Control of blood carnitine and carnitine acyltransferase in the perinatal period, New York, Academic Press, Inc., (in press). 11. Novak M. Wieser PB, Bach M, and Hahn P: Acteylcarnitine and free carnitine in body fluids before and after birth, Pediatr Res 13:10, 1979. 12. Bieber LL, Markwell MAK, Blair M, and Helmrath TA: Studies on the development of carnitine palmitoyl transferase and fatty acid oxidation in liver mitochondria of neonatal pigs, Biochem Biophys Acta 326:145, 1973.
1046
S c h i f f et al.
13. Schmidt-Sommerfeld E, Novak M, Penn D, Weiser PB, Buch M, and Hahn P: Carnitine and the development of newborn adipose tissue, Pediatr Res 12:660, 1968. 14. Schiff D, Chan G, and Andrew G: Metabolism of intravenously adminstered lipid in the newborn, in Stern L, editor: Intensive care in the newborn II., New York, 1978, Masson Publishing USA, Inc., p 267. 15. Andrew G, Chan G, and Schiff D: Lipid metabolism in the neonate, lIl. The ketogenic effect of Intralipid infusion in the neonate, J Pediatr 92:995, 1978. 16. McGarry JD, and Foster DW: An improved and simplified radioisotopic.assay for the determination of free and estertried carnitine, J Lipid Res 17:277, 1976. 17. Stone M, and Thorpe JL: A new technique for the investi-
The Journal of Pediatrics December 1979
18.
19.
20.
21.
gation of low density lipo-proteins in health and disease, Clin Chim Acta 14:812, 1966. Persson B: Determination of plasma acetoacetate and B-hydroxybutyrate in newborn infants by an enzymatic fluorometric method, Scand J Clin Invest 25:9, 1970. Cox RA, and Hoppel CL: Biosynthesis of carnitine and 4-N-trimethylaminobutyrate from lysine, Biochem J 136:1075, 1973. Frohlich J, Seccombe DW, Hahn P, Dodek P, and Hynie I: The effect of fasting on free and esterfied carnitine levels in human serum and urine, Metabolism 27:555, 1978. Postuma R, and Trevenen CL: Liver disease in infants receiving total parenteral" nutrition, Pediatrics 63:110, 1979.
Brief clinical and laboratory observations Full recovery from prolonged brainstem failure following intraventricular hemorrhage Joseph F. Pasternak, M.D., and Joseph J. Volpe, M.D.,* St. Louis, Mo.
P E R I V E N T R i C U L A R - I N T R A V E N T R 1 C U L A R HEMORRHAGE has been shown recently to be an extraordinarily c o m m o n lesion in the premature i n f a n t J ~ Although the majority of infants with hemorrhage survive, many die or sustain significant permanent neurologic disability. These severely affected infants usually exhibit distinct neurologic manifestations around the time of the hemorrhage, 1 ~ whereas those less severely affected usually have more subtle or, indeed, no abnormal neurologic findings, 1 ~, ~ Although it is generally recognized that a serious neonatal neurologic syndrome does not invariably presage a poor outcome, it is not clear from available From the Edward Mallinckrodt Department o[: Pediatrics and the Department of Neurology and Neurosurgel T (Neurology), Washington University School of Medicine, and the Division o f Neurology, St. Louis Children's Hospital. Supported in part b)~ The Allen P. and Josephine B. Green Foundation, M e x i c ~ Mo. Dr. Volpe is a recipient of a Research Career Development A ward (1-K4-HD 70608)frorn..the National Institutes t?f Health. *Reprint address: St. Louis Children's Hospital 500 S. Kingshighwa)', P. O. Box 14871, St. Louis, MO 63178.
information how serious a neurologic deterioration may occur and still be compatible with a favorable outcome. We report a premature infant with intraventricular hemorrhage who had a syndrome of essentially total brainstem failure but who recovered spontaneously and Abbreviations used CSF: cerebrospinal fluid CT: computerized tomography CPA~: continuous positive airway pressure EEG: electroencephalogram has made nearly normal developmental progress over the first 12 months. The particular importance of this case relates to the implicatidns of this clinical course for therapeutic and ethical decision-making in the manage,ment of the newborn infant with essentially total brainstem failure. CASE REPORT This female infant weighed 2,300 gm at birth after an uncomplicated 35-week gestation in a 23-year-old gravida 4, para 3 mother. Amniotic membranes ruptured spontaneously 48 hours prior to delivery and produced ciear find. Attempted induction of labor with pitocin failed on two successive days. On the
0022-3476/79/121046 + 04500.40/0 9 1979 The C. V. Mosby Co.
